Donor Bone Marrow Transplant With or Without G-CSF in Treating Young Patients With Hematologic Cancer or Other Diseases

Phase 3

Completed

Conditions: Childhood Myelodysplastic Syndromes
Childhood Acute Lymphoblastic Leukemia in Remission
Childhood Chronic Myelogenous Leukemia
Chronic Phase Chronic Myelogenous Leukemia
de Novo Myelodysplastic Syndromes
Previously Treated Myelodysplastic Syndromes
Childhood Acute Myeloid Leukemia in Remission
Juvenile Myelomonocytic Leukemia
Recurrent Childhood Acute Lymphoblastic Leukemia
Secondary Myelodysplastic Syndromes

Interventions: Procedure: allogeneic bone marrow transplantation
Other: laboratory biomarker analysis
Biological: filgrastim

Registration Number: NCT00450450

Lead Sponsor: Children's Oncology Group

Brief Summary: This randomized phase III trial is studying donor bone marrow transplant with or without G-CSF to compare how well they work in treating young patients with hematologic cancer or other diseases. Giving chemotherapy and total-body irradiation before a donor bone marrow transplant helps stop the growth of cancer or abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving methotrexate and tacrolimus or cyclosporine before and after transplant may stop this from happening. It is not yet known whether donor bone marrow transplant is more effective with or without G-CSF in treating hematologic cancer or other diseases.

Detailed Description: PRIMARY OBJECTIVE:

I. Compare improvement in event-free survival of patients with hematologic cancer or other diseases undergoing filgrastim (G-CSF)-stimulated bone marrow transplantation (BMT) vs conventional BMT.

SECONDARY OBJECTIVES:

I. Compare the incidence and time to engraftment in patients treated with these regimens.

II. Compare rates of acute and chronic graft-vs-host disease (GVHD) in patients treated with these regimens.

III. Correlate incidence of acute and chronic GVHD with absolute T-cell numbers, Th1 vs Th2 profile of T cells, dendritic cell populations, and T-regulatory cell content.

IV. Assess the impact of G-CSF-stimulated BMT as a stem cell source on hospital stay and treatment-related mortality at day 100 in patients treated with this regimen.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to risk (high vs intermediate vs standard).

CONDITIONING REGIMEN: Co-enrolled on COG-ASCT0431 or COG-AAML0531; Patients receive a conditioning regimen as defined on that treatment study.

ACUTE LYMPHOBLASTIC LEUKEMIA (ALL): Patients undergo total-body irradiation (TBI) twice daily on days -8 to -6. Patients receive thiotepa IV on days -5 and -4 and high-dose cyclophosphamide IV over 1 hour on days -3 and -2. Some patients with CNS leukemia or very high-risk ALL in first complete remission receive cranial radiotherapy.

ACUTE MYELOID LEUKEMIA, JUVENILE MYELOMONOCYTIC, CHRONIC MYELOGENOUS LEUKEMIA, OR MYELODYSPLASTIC SYNDROMES: (myeloid malignancies) Patients receive busulfan IV over 2 hours every 6 hours on days -9 to -6 and high-dose cyclophosphamide IV over 1 hour on days -5 to -2.

GRAFT-VS-HOST DISEASE (GVHD) PROPHYLAXIS: Co-enrolled on COG-ASCT0431 or COG-AAML0531: Patients undergo GVHD prophylaxis as defined on that treatment study.

ALL: Patients receive tacrolimus IV or orally beginning on day -2 and continuing until day 42, followed by a taper until day 98. Patients also receive methotrexate IV on days 1, 3, and 6.

MYELOID MALIGNANCIES: Patients receive cyclosporine IV continuously or orally beginning on day -1 and continuing until day 42 or day 50, followed by a taper for 8-16 weeks. Patients also receive methotrexate IV on days 1, 3, 6, and 11.

ALLOGENEIC BONE MARROW TRANSPLANTATION (BMT): Patients are randomized to 1 of 2 transplantation arms.

ARM I: Patients undergo filgrastim (G-CSF) -stimulated allogeneic BMT on day 0.

ARM II: Patients undergo conventional allogeneic BMT on day 0.

After completion of study treatment, patients are followed at 1 year and then annually for 5-10 years.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 27

Inclusion Criteria

Diagnosis of hematologic cancer or other disease, including any of the following:
- Chronic myelogenous leukemia in first or second chronic phase
- Acute lymphoblastic leukemia (ALL), meeting any of the following criteria:
  - Relapsed ALL enrolled on a Children's Oncology Group (COG) relapse clinical trial OR received ≥ 1 round of reinduction therapy (4-6 weeks) and 1 round of intensive consolidation chemotherapy (3-6 weeks)
  - ALL in second complete remission (CR)* after a bone marrow, extramedullary, or combined bone marrow and extramedullary relapse
  - Very high-risk ALL in first CR, defined as any of the following:
    - Philadelphia chromosome-positive ALL
    - Hypodiploidy (< 44 chromosomes)
    - Mixed lineage leukemia rearrangement
    - Induction failure
- Acute myeloid leukemia in first or second CR
  - Induction therapy must be completed
- Juvenile myelomonocytic leukemia
- Myelodysplastic syndromes
No clinically evident CNS or extramedullary disease
No blasts seen on cerebrospinal fluid cytospin
Post-relapse reinduction therapy must be completed
Not planning to receive reduced-intensity conditioning regimen
Not planning to receive a graft that has undergone T-cell depletion
No Down syndrome
Matched sibling donor must be available and must be enrolled on ASCT0631D companion study
Karnofsky performance status (PS) 60-100% (patients > 16 years of age) OR Lansky PS 60-100% (patients ≤ 16 years of age)
AST or ALT < 5 times upper limit of normal for age
Bilirubin < 2.5 mg/dL (unless due to Gilbert's syndrome)
Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR serum creatinine base on age and/or gender as follows:
- 0.4 mg/dL (1 month to < 6 months of age)
- 0.5 mg/dL (6 months to < 1 year of age)
- 0.6 mg/dL (1 to 2 years of age)
- 0.8 mg/dL (2 to < 6 years of age)
- 1.0 mg/dL (6 to < 10 years of age)
- 1.2 mg/dL (10 to < 13 years of age)
- 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)
- 1.7 mg/dL (male) or 1.4 mg/dL (female) (≥ 16 years of age)
Shortening fraction ≥ 27% by echocardiogram OR LVEF ≥ 50% by radionuclide angiogram
FEV_1, FVC, and DLCO ≥ 60% OR meets the following criteria (for patients unable to cooperate for pulmonary function tests):
- No evidence of dyspnea at rest
- No exercise intolerance
- No requirement for supplemental oxygen therapy
Not pregnant or nursing
No known HIV
No known uncontrolled fungal, bacterial, or viral infections
- Patients acquiring fungal disease during induction therapy may proceed if they have a significant response to antifungal therapy with no or minimal evidence of disease remaining by CT scan
No prior allogeneic or autologous stem cell transplantation

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm II	laboratory biomarker analysis	Patients undergo conventional allogeneic bone marrow transplantation on day 0.
Arm II	allogeneic bone marrow transplantation	Patients undergo conventional allogeneic bone marrow transplantation on day 0.
Arm I	filgrastim	Patients undergo filgrastim (G-CSF)-stimulated allogeneic bone marrow transplantation on day 0.
Arm I	allogeneic bone marrow transplantation	Patients undergo filgrastim (G-CSF)-stimulated allogeneic bone marrow transplantation on day 0.
Arm I	laboratory biomarker analysis	Patients undergo filgrastim (G-CSF)-stimulated allogeneic bone marrow transplantation on day 0.

Primary Outcome Measures

Name	Time	Method
Estimated Two-year Event-free Survival (EFS)	at 2 years	EFS is defined as relapse or treatment-related mortality (TRM). relapse is defined by either morphological or cytogenetic evidence of ALL consistent with pre-transplant features.

Secondary Outcome Measures

Name	Time	Method
Estimated Graft Failure Rate	Up to 10 years	Primary graft failure is defined as the failure to achieve an absolute neutrophil count of more than 5000 per cubic millimeter for at least three consecutive days by Day +42.
Estimated Percentage of Chronic Graft-versus-host Disease (cGVHD)	18 months post-transplant	cGVHD definition is based on BMT CTN MOP SEPT. 2005; outlined in Protocol Appendix III.
Estimated Incidence of Grade III-IV Acute Graft-versus-host Disease (aGVHD)	Up to 3 months	Stage III-IV aGVHD is defined as: Stage 0-3 skin, with Stage 2-3 liver, or Stage 2-3 GI; OR Stage 4 skin, liver or GI involvement.
Estimated Median Time to Neutrophil Engraftment	Up to 10 years	Median Time from transplant to neutrophil engraftment
Estimated 100-day Transplant Related Mortality (TRM) Percentage	100 days	Death in a patient after transplant due to protocol treatment is defined as an TRM.
Estimated Median Length of Initial Hospitalization	Up to 10 years	Estimated and compared between randomization arms using the Wilcoxon rank-sum test.

Trial Locations

Locations (21): Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Childrens Memorial Hospital
🇺🇸
Chicago, Illinois, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
Primary Children's Medical Center
🇺🇸
Salt Lake City, Utah, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
University of Texas Southwestern Medical Center
🇺🇸
Dallas, Texas, United States
New York Medical College
🇺🇸
Valhalla, New York, United States
Johns Hopkins University
🇺🇸
Baltimore, Maryland, United States
Children's Oncology Group
🇺🇸
Arcadia, California, United States
University of California San Francisco Medical Center-Parnassus
🇺🇸
San Francisco, California, United States
Children's Hospital Colorado
🇺🇸
Aurora, Colorado, United States
Riley Hospital for Children
🇺🇸
Indianapolis, Indiana, United States
Indiana University Medical Center
🇺🇸
Indianapolis, Indiana, United States
Kosair Children's Hospital
🇺🇸
Louisville, Kentucky, United States
The Childrens Mercy Hospital
🇺🇸
Kansas City, Missouri, United States
C S Mott Children's Hospital
🇺🇸
Ann Arbor, Michigan, United States
University of North Carolina
🇺🇸
Chapel Hill, North Carolina, United States
Vanderbilt-Ingram Cancer Center
🇺🇸
Nashville, Tennessee, United States
Hackensack University Medical Center
🇺🇸
Hackensack, New Jersey, United States
University of Nebraska Medical Center
🇺🇸
Omaha, Nebraska, United States